Composition for treatment of gastro-intestinal disorders

ABSTRACT

A pharmaceutical composition useful for the treatment of gastrointestinal disorders comprising a diethylaminoethyl cross-linked dextran anion exchanger and a pharmaceutical carrier or another therapeutic agent and a method of treating gastro-intestinal disorders in mammals by the oral administration of such a composition.

United States Patent Inventors Edmund S. Granatek;

Alphonse P. Granatek, both 01 Baldwlnsville, N.Y.

Appl. No. 605,231

Filed Dec. 28, 1966 Patented Nov. 30, 1971 v Assignee Bristol-MyersCompany New York, N.Y.

COMPOSITION FOR TREATMENT OF CASTRO- [56] References Cited UNITED STATESPATENTS 2,554,072 5/1951 Sullivan et al. 424/79 2,581,035 ll1952 Martinet a1. 424/79 3,002,823 10/1961 Flodin et al. 23/293 3,042,667 7/1962Flodin et al 260/209 3,107,203 10/1963 Baumgarten et al. 195/663,364,111 1/1968 Morii et al. 167/55 Primary Examiner-Albert T. MeyersAssistant Examiner-Daren M. Stephens Attorneys-Curtis W. Carlton,Richard H. Brink, Robert B.

Simonton and Herbert W. Taylor, Jr.

ABSTRACT: A pharmaceutical composition useful for the treatment ofgastro-intestinal disorders comprising a diethylaminoethyl cross-linkeddextran anion exchanger and a pharmaceutical carrier or anothertherapeutic agent and a method of treating gastro-intestinal disordersin mammals by the oral administration of such a composition.

COMPOSITION FOR TREATMENT OF CASTRO- INTESTINAL DISORDERS lt is knownthat pepsin contributes substantially to ulcer formation in thegastro-intestinal tract of mammals. Therefore, an important part ofulcer therapy is to reduce the amount of pepsin in the stomach.Heretofore only a limited number of pepsin inhibitors were known.Therefore, an object of the present invention is to provide apharmaceutical composition useful for the treatment of ulcers of thegastro-intestinal tract. Another object of this invention is to providea method of treating ulcers of the gastro-intestinal tract in mammals.

These and other objects which will become apparent as this specificationproceeds are accomplished by the provision according to the presentinvention of a pharmaceutical composition comprising a diethylaminoethylcross-linked dextran anion exhanger and a pharmaceutical carrier.

The diethylaminoethyl cross-linked dextran anion exchanger used in thecompositions of this invention is marketed by Pharmacia Uppsula, Sweden,under the trade name DEAE-Sephadex. The anion exchanger is a weaklybasic anion exchanger and is the diethylaminoethyl derivative of apolymer produced from dextran by cross-linking the linear polysaccharidechains to a threedimensional network, which acts as a molecular sieve.The polymer is also marketed by Pharmacia Uppsula, Sweden, under thetrade name Sephadex. In the diethylaminoethyl derivative, thediethylaminoethyl groups are attached at random by ether linkages to theglucose residues constituting the polysaccharide chains. Thediethylaminoethyl cross-linked dextran anion exchanger employed in thecompositions of this invention is fully described by B. Spross et al.,Acla Pharmaceutica Suecica Vol. 2, No. l, p. 1 (Feb. 1965).

Quite unexpectedly, it was discovered that diethylaminoethylcross-linked dextran anion exchanger has antipepsin activity. The anionexchanger in effect neutralizes the effect of pepsin, making it usefulfor the treatment of ulcers in mammals, when administered in aneffective amount.

The compositions of this invention comprise not more than about 200mgJkg. per dosage unit and preferably from about I to about 200 mg./kg.of diethylaminoethyl cross-linked dextran anion exchanger together witha suitable carrier. The carrier may be either a solid or liquid and thecompositions can be in the form of tablets, capsules, powders, granulesor suspensions. The compositions can contain suitable preservatives,coloring and flavoring agents. Some examples ofthe carriers which can beused in the preparation of the compositions of this invention aregelatin capsules, sugars, cellulose derivatives such as sodiumcarboxy-methylcellulose, gelatin, talc, magnesium stearate, vegetableoil, such as peanut oil, etc., liquid petroleum, glycerin, sorbitol,ethanol, agar and water. The carrier may serve as a binder and thecomposition may be tabletted. If the carrier is a gelatin capsule, thediethylaminoethyl cross-linked dextran anion exchanger may beencapsulated into the gelatin capsule by conventional means. If a liquidcarrier is used, the composition may be in the form ofa suspension.

The compositions of the present invention may also contain othertherapeutic agents, e.g., antacids, antispasmodics, anticholinergics andthe like. Representative of the antacids are aluminum hydroxide,magnesium hydroxide, aluminum glycinate, calcium carbonate, complexes asdescribed in U.S. Pat. No. 3,200,136 and the like.

Administration of the compositions of this invention to mammals orallyin an effective amount is a useful method of treating gastro-intestinalulcers.

The following examples are intended to illustrate the inven tion claimedherein without unduly restricting it.

EXAMPLE 1 This example demonstrates the antipepsin activity of thediethylaminoethyl cross-linked anion exchanger. The followingexperiments were carried out.

1. Five grams of gelatin was dissolved in 50 ml. of water, held at 37 C.for 1 hour and then allowed to stand overnight at ambient temperature.Result: The system set up to a stiff gel.

2. The above l repeated with 1 gram of DEAE-Sephadex A-25 added. Result:The system set up to a stifi gel.

3. The above, (I), was repeated with 1 gram of pepsin added. Result: Thesystem remained fluid with no gel formation.

4. The above, l was repeated with 1 gram of pepsin plus l gram ofDEAE-Sephadex A-25 added. Result: The system set up to a stiff gel.

From a comparison of the results of the foregoing experiments, it can beconcluded that the diethylaminoethyl crosslinked anion exchangerinhibits peptic activity.

EXAMPLE 2 Two hundred grams of finely powdered DEAE-Sephadex A-25 aremixed with 200 grams of dried starch. The mixture is tested according tothe procedure described in example 1 and is found to exhibit antipepticactivity.

EXAMPLE 3 Two hundred grams of finely powdered DEAE-Sephadex A-25 aremixed with grams dried finely powdered aluminum hydroxide and 100 gramsof dried starch. The mixture is tested according to the proceduredescribed in example I and is found to exhibit antipeptic activity.

EXAMPLE 4 Ingredients Amounts per tablet, mg.

DEAE-Sephadex A-25 Lactose, powdered Sucrose, powdered Talc Magnesiumstcarate The DEAE-Sephadex, lactose and sucrose are mixed and screenedthrough a 60-mesh U.S. standard screen. The screened mixture is thengranulated with an alcoholic ethyl cellulose solution and the wettedmass is screened through an 8-mesh U.S. standard screen. The granulesare dried and passed through a lZ-mesli screen. These granules are thenmixed with the tale, magnesium stearate, peppermint and spearmint andcompressed into tablets.

Two or more tablets are administered once a day.

EXAMPLE 5 Antacid Suspension Manufacturing Instructions l. Assemble allequipment to be used in the production of EXAMPLE 7 the product. Cleanand sterilize the equipment. Include all hoses, filters, scoops, etc.,as well as the tanks and larger pieces of equipment. The manufacturingarea Ingredients m n should be swabbed with -percent phenol solution.All 5 personnel in the area should wear sterile caps, gowns,DEAE-SeiJhadn A45 1 1. masks d gloves Sodium saccharin 0.025 gm.D-sorbitol 2.000 gm. 2. To a clean (not sterile) tank, add 60 percent ofthe final Mcmylpmbcn (25 gm. bath volume of Purified Water U.S.P.Propylaparaben 0.02s gm. 3. With agitation add the sodium hydroxide,methylparaben 1O Svdivm melahisulphile 0,100 s Oil of Peppermint 0.0)gm.

nd r ra n aninupeopylpa be to the batching tank Mix for Purified Wmusyuqs 00000 ml.

4. With continued agitation add the saccharin sodium, sodium cydamateand magneslum gluconme' Commue agna' 15 The parabens are dissolved in ISml. of hot water and to this for mnjutes or a clear Sohmon r.esults'added the sorbitol, saccharin and sodium metabisulphite the solimon fromstep 4 through a which had previously been dissolved in 20 ml. of water.The equipped with E0 pads. Collect the filtrate in a sterileDEABsephadex is added to the above solution and batching tank Reta!" thei filter so that u may be thoroughly mixed. The oil of peppermint isthen added and the used to prepare filtered purified water U.S.P. ascalled for 20 preparation is brought up to volume with purified water.

in Subsequemsteps' T t bl f l ad in ter dfo rtimes dail 6. To thefiltered solution from step 5, add the sterile we a espoons u are m ls eu y.

dimethylpolysiloxane mixture, the aluminum hydroxide EXAMPLE 8 gel,DEAE-Sephadex and the magnesium hydroxide paste with rapid agitation.Containers may be rinsed with filtered purified water U.S.P. equivalentto 4 percent of the total batch volume.

Aluminum Hydroxide-Magnesium Hydroxide Antacid Sus ension Use sterileutensils for the transfer. Maintain agitation until P a smooth, uniformdispersion has been obtained. Formula: Per um 7. Pass the suspensionthrougha sterile 6-inch or 8-inch Premier mill. Adjust the tank p.s.i.with air pressure (sterile) DEAESePhadeX A45 400000 gm or with nitrogento maintain 5 p.s.i. on the mill head. Ad- Methyl Paraben. U.S.P..micmnized 0.700 1", just the clearance of the rotor to 0.010 on the8-inch mill Z'ZP z ij g l gm- O lUm ICC arm. or 0.006 on the 6-mch mill.Temperature of the milled Sodium sucaryl HM gm suspension should notexceed 86 F. (30 C.). Begin cool- Aluminum O ide as Aluminum Hydroxideing of the sterile receiving tank as the milling starts. We! TA BakuChcmiwl P Y- 8. Rinse the batching tank with a volume of filteredpurified W' gm Magnesium Hydroxide as Merck water U.S.P. equal to 8percent of the final batch volume Hydmmugnu MM [ml/3,4 4M0 8m and add tothe batch. Magnesium Gluconate l0.00 gms. 9. Add the oil of peppermintto the batch and agitate for l5 40 cuthllxymflhyl Ccllulvss 125 gmminues Oil of Pep ermint, U.S.P. (H0 ml.

. Purified Water. U.S.P. qs I.()U0.Ul) ml. l0. Agltate the batch undervacuum for 20 minutes. Release with nitrogen or filtered air. I 1. Checkfinal volume and if necessary add sufficient fil- ManufacturingInstructions tered purified water U.S.P. to the batch to bring it up toL To 400 mL of purified water add the methyl ig i g I f 20 th 1 paraben,propyl paraben, sodium saccharin, sodium sucaryl gi ate un er vacuum orminutes en re ease W1 and magnesium gluconam nitrogen or filtered airand hold for filling. Take final samwith mild agitation heat to 700 andhold a this ples' perature until solution is obtained.

l3. Transfer product to filling line using nitrogen or filtered 3 Coolto C using cooling water in the tank jacket and air. Pass the productthrough a 40-mesh screen on the to 400 ml. 'Iith Purified water U51 "1to the finmg Befor? i the tank be 4. Pass the solution through a sterileErtel filter equipped agitated for 30 'f AglPauon Should commlfed withE0 pads and collect into a sterile batching tank. throughout the fillingoperation. Do not agitate at high 55 5. Pass an additional quantity ofpurified water USP. speed through the filter sufficient to collect 300ml. of filtrate and place in a sterile holding tank. EXAMPLE 6 6. Swabthe exterior of the drums containing the wet gels with 5 percent W/Vphenol solution.

mediums Amoumspenabmmg 7. To the filtered solution in the batching tank(step 4),

slowly add the DEAE-Sephadex aluminum hydroxide and DEABSCPMMX A45 50Mmagnesium hydroxide gels with rap d agitation. tJse sterile utensils forthis transfer. Maintain agitation until a Magnesium stearate 2.5 smooth,uniform dispersion has been obtained.

8. Remove 200 ml. of the filtered water from the holding tank (step 5)and dissolve the carboxymethyl cellulose in The DEAE-Sephadex and halfthe amount of starch are it with rapid agitation in asterile vessel.mixed and screened through a 60-mesh U.S. standard screen. 9. Withagitation, slowly add the carboxymethyl cellulose The screened mixtureis then granulated with an alcoholic solution to the suspension fromstep 7. Up to 20 ml. of the ethyl cellulose solution and the wetted massscreened through filtered water left in the holding tank may be used foran 8-mesh U.S. standard screen. The granules are dried and rinsing,continue to mix rapidly until uniformly dispersed. passed through al2-mesh screen. These granules are then 10. Pass the suspension througha sterile Eppenbach mixed with the remaining starch and magnesiumstearate and micromill with the micrometer set at 2(0.002-inchcompressed into tablets. clearance) and the Rheostat set at 100. Coolingwater One tablet is administered twice a day. must be used in the jacketof the mill.

l l. Deaerate using the Spray Nozzle" process. Up to 60 ml. of thefiltered water remaining in the holding tank (step 5) may be used forrinsing.

12. Add the oil of peppermint and sufficient filtered water from theholding tank (step 5) to bring the batch up to 5 final volume.

13. Agitate at a moderate speed for minutes being careful not toincorporate air into the suspension.

EXAMPLE 9 l0 Chewable Antacid Tablet Manufacturing lnstructions for1,000 Tablets 1. Prepare 266.0 grams of 5 percent (w/w) starch paste byheating 13.3 grams of corn starch dispersed in 252.7 ml. of purifiedwater, U.S.P., to boiling. Sufficient agitation should be used duringthis step to avoid scorching. Remove heat and maintain agitation untilcooled to 25 C. Add sufficient purified water, U.S.P., to bring theweight up to 266.0 grams and mix to obtain a homogenous paste. 2. Placethe DEAE-Sephadex, aluminum hydroxide, magnesium hydroxide, mannitol,urea, sodium sucaryl and sodium saccharin in a pony pan and blend atslow speed for 15 minutes.

. Pass the blend through a Fitzmill at high speed with impact forwardusing a MOO screen.

4. Return the milled material to the pony pan and continue mixing forone-half hour.

. With agitation remaining at low speed, rapidly add all of the starchpaste from step 1 and mix until a uniform dispersion is obtained. Themix appears dry at this point but usually contains enough moisture toform the granulation. if necessary, additional water may be added tofacilitate the formation of the strands of granulation described in thenext step.

6. Pass the mix through a Stokes oscillator, with funnel removed, usinga 6-mesh stainless steel screen and collect directly on drying trays. Ifstrands of granulation are not being formed, additional water must beadded to the mix.

7. Spread the granulation evenly on the trays and dry in a Stokes ovenat 38 C. until the moisture content is 4.5 to 5.5 percent.

8. Mill using a combination of screen, speed, and blade adjustment whichwill produce the greatest yield of 30- to 5 60-mesh granules.

9. Separate the granules retained on a 60-mesh screen, add

5.48 percent magnesium stearate and hold.

10. To the fines passing through a 60-mesh screen add 5.48

percent magnesium stearate and blend thoroughly.

l l. Slug at a weight of 0.470 grams using one-half inch, flat punchesto a hardness of 5 to 7 kg. Reduce the slugs to 30- to 60-mesh granulesand repeat the process until not more than 15 percent nor less than 10percent of fines passing through a 60-mesh screen remain.

LII

l2. Combine the lubricated granules from step 9 with the granules andfines from step 1 I. Add the flavors and blend thoroughly for 30minutes.

13. Tablet using five-eighth inch, fiat, beveled edge punches to ahardness of 1 1 kg. or one-half inch square, concave punches to ahardness of 9 to 10 kg. (Strong-Cobb-Arner Tester).

EXAMPLE l0 Chewable Tablets with Antiflatulant Formula: Per Table!DEAE-Sephadex A-ZS 0.5000 gms. Aluminum Hydroxide Gel, Dried, U.S.P.0.3120 gm. Magnesium Hydroxide, N.F. 0.0936 gm. Mannitol, N.F. 0.30M gm.Urea, N.F. 0.0600 gm. Sodium Cyclamate, N.F. 0.0200 gm. SodiumSaccharin, U.S.P. 0.0020 gm. Corn Starch, U.S.P. 0.0160 gm.Polyvinylpyrrolidone 0.0080 gm. Flavors 0.0!30 gm. Magnesium Stearate,U.S.P. 0.0340 gm. Dimethylpolysiloxane 0.0200 gm. Silicone Dioxide (finepowder) 0.0l25 gm.

Total Weight [.3925 gms.

Manufacturing lnstructions l. Dissolve the dimethylpolysiloxane inmethylene chloride using 2 ml. of methylene chloride for each gram ofmedical fluid.

2. With agitation, add the solution from step I to the silicone dioxidein a pony pan. Mix until uniformly dispersed.

3. Dry until free of methylene chloride. 4. Pass the mannitol, urea anddried silicone dioxide from step 3 through a Fitzmill equipped with aOO-screen, impact forward, high speed.

5. Place the milled material from step 4 in a blender with the aluminumhydroxide, magnesium hydroxide, sodium cyclamate and sodium saccharin.Blend for 30 minutes.

6. a. With agitation, dissolve the PVP in about two-thirds of thepurified water U.S.P. required to make the paste.

(Amount of purified water U.S.P. for paste should be 20 ml. per gram ofcorn starch).

b. Heat the PVP solution to boiling.

c. Disperse the corn starch in the remaining one-third of the water.

d. Add the starch-water dispersion to the hot PVP solution with mixing.Continue to mix and heat until a translucent gel results.

7. With agitation at low speed, add the starch paste to the powder blendin a pony pan. Mix well to form a uniform wet granulation. If necessary,this step may be carried out in two or more pan loads.

8. Spread the granulation evenly on trays, breaking up the large lumpsby hand, and dry at F. (38 C.) for l0 hours. NOTE: Moisture content ofthe dried granules must be from 4.5 to 5.5 percent. Extreme caution mustbe taken no! 10 overdry this granulation.

9. Pass the dried granules through a Fitzmill equipped with a Example Il Antacid Chewable Soft Gelatin Capsules Formula: Per CapsuleDEAE-Sephadex A-25 0.250 gm. Soluble Buffer Antacid.

micropulverized 0.425 gm. Aluminum Hydroxide-Magnesium Carbonate,micropulverized Codried Gel.

FMA-I I Powder. Reheis 0.425 gm. Magnesium Trisilicate Powder 0100 gm.Soy Bean Oil Refined 0.480 gm. mixture used Lecithin. Soya 0.0l5 gm. toq.s. Sodium Lauryl Sulfate U.S.P. 0.0075 gm. Mannitol N.F..

mieropulverized 0. I gm. Urea. micropulvcrized 0.080 gm. SodiumCyclamate N.F..

micropulverized 0.0768 gm. Sodium Saccharin N.F.. 0.00768 gm. PeppermintNatural Flavor. Powder 0.006 gm. Preparation of Soluble Buffer Antacid:Per I20 ml. Gluconic Acid. Technical 50% Grade Sufficient AluminumHydroxide Magnesium Hydroxide NF. Powder 5.60l grams ManufacturingInstructions for Soluble Buffer Antacid I. To a sterilized tank. add 16liters of deionized water and the gluconic acid.

2. With agitation, heat the mixture to 80 C.

3. With continued agitation, slowly add the magnesium hydroxide. (Fastaddition will result in frothing.)

4. With continued agitation, slowly add the aluminum hydroxide.

5. Maintain agitation and temperature at 90l00 C. for l hour. At thispoint. the solution is light yellow in color and slightly hazy inappearance. Check pH. (Should be greater than 7.6)spray dry. evaporateto dryness or lyophilize.

Manufacturing Instructions for Antacid Chewable Soft Gelatin Capsules I.With agitation in a suitable container dissolve the lecithin in the soybean oil.

2. With agitation incorporate the sodium lauryl sulfate.

3. With agitation incorporate all the ingredients.

4. Pass the suspension through a premier mill.

5. Deaerate. 6. Fill into the smallest size capsules possible. using asoft gelatin encapsulating machine.

Example 12 Antacid Chewable Soft Gelatin Capsules Formula: Per CapsuleDEAE-Sephadex A-25 0.40 gm. Soluble Buffer Antacid micmnized L79 gms.Soy Bean Oil Refined 0.480 gram mixture used Lecithin. Soya 0.0 l 5 gramto q.s. Sodium Lauryl Sulfate U.S.P. 0.0075 gm. Mannitol N.F..micropulverized 0. I00 gm. Urea. micropulverized 0.080 gm. SodiumCyclamate N.F..

micropulverized 0.768 gm. Sodium Saccharin N.F. 0.00768 gm. PeppermintNatural Flavor, Powder 0.006 gm.

Manufacturing Instructions I. With agitation in a suitable containerdissolve the lecithin in the soy bean oil.

2. With agitation incorporate the sodium lauryl sulfate.

3. With agitation incorporate all the ingredients.

4. Pass the suspension through a premier mill.

5. Deaerate.

6. Fill into the smallest size capsules possible. using a soft gelatinencapsulating machine.

While this invention has been described in terms of its preferredembodiment, those skilled in the art will appreciate that modificationscan be made.

What is claimed is:

l. A pharmaceutical composition for the treatment of gastro-intestinaldisorders comprising a diethylaminoethyl crosslinked anion exchanger andan antacid selected from the group consisting of aluminum hydroxide,magnesium hydroxide, aluminum glycinate and calcium carbonate.

2. A pharmaceutical composition for treatment of gastro-intestinaldisorders according to claim 1, wherein said antacid is aluminumhydroxide.

3. A pharmaceutical composition for treatment of gastro-intestinaldisorders according to claim 1. wherein said antacid is magnesiumhydroxide.

4. The pharmaceutical composition for treatment of gastrointestinaldisorders of claim I in unit dosage form for oral administration.

5. The pharmaceutical composition for treatment of gastrointestinaldisorders of claim 1 in the form of a dosage unit tablet.

6. The method of treating gastro-intestinal ulcers in mammals whichcomprises orally administering an effective amount of a compositioncomprising diethylaminoethyl crosslinked dextran anion exchanger and anantacid selected from the group consisting of aluminum hydroxide,magnesium hydroxide, aluminum glycinate and calcium carbonate.

7. The method of claim 6 wherein said antacid is aluminum hydroxide.

2. A pharmaceutical composition for treatment of gastro-intestinaldisorders according to claim 1, wherein said antacid is aluminumhydroxide.
 3. A pharmaceutical composition for treatment ofgastro-intestinal disorders according to claim 1, wherein said antacidis magnesium hydroxide.
 4. The pharmaceutical composition for treatmentof gastro-intestinal disorders of claim 1 in unit dosage form for oraladministration.
 5. The pharmaceutical composition for treatment ofgastro-intestinal disorders of claim 1 in the form of a dosage unittablet.
 6. The method of treating gastro-intestinal ulcers in mammalswhich comprises orally administering an effective amount of acomposition comprising diethylaminoethyl cross-linked dextran anionexchanger and an antacid selected from the group consisting of aluminumhydroxide, magnesium hydroxide, aluminum glycinate and calciumcarbonate.
 7. The method of claim 6 wherein said antacid is aluminumhydroxide.